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Coordinated Regulation of Virulence Genes in C. neoformans

新型隐球菌毒力基因的协调调控

基本信息

批准号：
8080553
负责人：
ANDREW ALSPAUGH
金额：
$ 30.46万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2012-03-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8080553
关键词：
Address Adenylate Cyclase Bioinformatics Biological Process Carbon Cell physiology Cells Cellular Stress Cellular Stress Response Communicable Diseases Consensus Sequence Cryptococcus neoformans Cyclic AMP Cyclic AMP-Dependent Protein Kinases Elements Environment GTP-Binding Protein alpha Subunits, Gs Gene Expression Genes Genetic Transcription Growth Factor Homologous Gene Human Infection Infectious Agent Mediating Melanins Organism Pathogenesis Pathway interactions Phosphorylation Polysaccharides Production Promoter Regions Proteins Regulation Regulatory Element Research Personnel Role Series Signal Pathway Signal Transduction Signal Transduction Pathway Signaling Molecule Source Stimulus Stress Testing Transcription factor genes Virulence Yeasts capsule comparative environmental change fungus gene function man microbial microorganism novel pathogen research study response transcription factor

项目摘要

Project Summary. To survive within the hostile environment of the infected host, pathogenic microorganisms must be able to sense and adapt to changing environmental conditions. This adaptation requires a coordinated regulation of multiple factors for growth and survival. Like many infectious agents, the human fungal pathogen Cryptococcus neoformans uses the conserved signaling molecule cyclic AMP (cAMP) to regulate its response to external stresses. The central components of cAMP signal transduction pathways are highly conserved among microorganisms. However, the main hypothesis of this proposal is that the upstream activating signals and the downstream effectors of cAMP are functionally specialized in microbial pathogens. This specialization allows pathogenic organisms to use cAMP signaling to control their virulence potential. Increased cAMP production activates a series of protein interactions that allows C. neoformans to adapt to the host environment. Specifically, the C. neoformans cAMP pathway regulates the induction of capsule and melanin, two cellular factors required for pathogenesis. This regulation occurs at the level of transcription. Therefore, the experiments of this proposal will identify trans- and cis-acting regulatory elements that mediate the effect of cAMP on the transcription of capsule-associated genes. Moreover, defining the regulatory networks controlled by cAMP-dependent transcription factors will allow us to explore broad issues in environmental sensing, cellular stress, and microbial virulence. Specific Aim 1 proposes bioinformatic and transcriptional profiling approaches to identify transcription factors that control C. neoformans capsule gene expression. Specific Aim 2 outlines detailed testing of selected transcriptional regulators to define their role in capsule induction. Experiments in Specific Aim 3 will define the direct and indirect target genes of the transcription factors identified in the first two Aims.

项目摘要。为了在受感染宿主的恶劣环境中生存，致病菌微生物必须能够感知并适应不断变化的环境条件。这适应需要对生长和生存的多种因素进行协调调节。像许多人一样传染性病原体，人类真菌病原体新型隐球菌使用保守的信号分子环磷酸腺苷 (cAMP) 调节其对外部应激的反应。中央 cAMP 信号转导途径的组成部分在微生物中高度保守。然而，该提案的主要假设是上游激活信号和 cAMP 下游效应器在功能上专门针对微生物病原体。这专业化允许病原生物利用 cAMP 信号传导来控制其毒力潜在的。 cAMP 产量的增加会激活一系列蛋白质相互作用，使 C. 新型隐球菌适应宿主环境。具体而言，新型隐球菌 cAMP 途径调节荚膜和黑色素的诱导，这是发病机制所需的两种细胞因子。这调控发生在转录水平。因此，本提案的实验将鉴定介导 cAMP 对胶囊相关基因的转录。此外，定义受控的监管网络通过 cAMP 依赖性转录因子的研究将使我们能够探索环境中的广泛问题传感、细胞应激和微生物毒力。具体目标 1 提出生物信息学和转录分析方法来识别控制新型隐球菌的转录因子胶囊基因表达。具体目标 2 概述了所选转录的详细测试调节器来定义它们在胶囊诱导中的作用。具体目标 3 中的实验将定义前两个目标中确定的转录因子的直接和间接靶基因。